DESCRIPTION: Non-steroidal anti-inflammatory drugs are heavily consumed world-wide due to their great efficacy to inhibit fever, inflammation and pain. The major side effects of these drugs relate to their gastrointestinal (GI) toxicity resulting in significant morbidity/mortality of chronic NSAID users. Although NSAIDs inhibit cyclo-oxygenase (COX) activity and the synthesis of GI-protective prostagalandins, it is also clear that they topically induce acute surface injury to the GI mucosa. The proposed experiments are related to the following observations made by our laboratory: 1) that the mucosal surface of the GI tract has hydrophobic (acid-resistant) surface properties due to the presence of an extracellular lining of zwitterionic phospholipids; 2) that NSAIDs form a chemical association with zwitternoic phospholipids; and 3) that NSAIDs preassociated with phospholipids have low GI toxicity and enhanced therapeutic activity. Based on these observations we have designed experiments to investigate whether NSAIDS induce topical injury by attenuating the phospholipid hydrophobic surface barrier of the stomach, and how the above surface changes relate to the drugs' inhibitory activity. This will be accomplished by administering selected NSAIDS (in the unmodified and phospholipid-associated state) to either wild-type or COX-1 deficient rodents and assessing the dose- and time-dependence in the reduction in surface barrier properties (gastric contact angles) and COX activity. We will determine if the phospholipid-associated NSAIDs have a greater ability than unmodified NSAIDs to inhibit the COX-2 activity of cells selectively expressing this isoform, either naturally or by genetic manipulation. We will investigate the molecular interaction of NSAIDs with phospholipids by Nuclear Magnetic Resonance and study the effect of these drugs on the hydrophobicity and fluidity of membranes and their ability to undergo fusion employing fluorescent probes. Lastly, we will investigate the ability of NSAIDs, that are secreted in the bile, to block the ability of biliary lecithin to bind to and detoxify bile salts, using both in vivo and in vitro systems, in an attempt to understand the mechanism that these drugs induce injury to the small intestinal mucosa.